This competing renewal uses MRI to quantitate structure of three inter- related brain systems: temporolimbic, basal ganglia and heteromodal (polymodal) association cortex. Previous work done by our group and others implicates these three systems as structurally or functionally abnormal in schizophrenia and affective disorder, and in some cases associated with clinical symptoms. The proposed project employs advanced MRI methods in a new sample to examine the structure of these key brain systems. These methods are available in our lab, and allow us to attempt to replicate our findings and to follow-up on hypotheses generated by work in the first three years of the grant. Hypotheses will be explored both within and across key regions. Preliminary data gathered with our new MRI methods show feasibility, and will allow us to study novel cortical areas, providing supportive evidence for a hypothesis of disproportionate reduction of volume in, and disruption of normal asymmetries within heteromodal association cortical grey matter regions in schizophrenia. The overall project will allow a systematic investigation of related multi-system neural deficits. The relevance of the above measures in discriminating schizophrenia from affective disorder will be examined in well- characterized and individually matched subjects consisting of 40 schizophrenics, 80 bipolars (half with psychotic symptoms) and 40 normal controls. The ultimate aim is to identify putative diagnostic markers and to aid subtyping.